Triglyceride is the predominant component of blood neutral lipid and, physiologically, is utilized as an energy source in the peripheral tissue. Hypertriglyceridemia, involving an increased blood triglyceride level, is thought to be a risk factor of arteriosclerosis, and actually is employed as a diagnostic standard for metabolic syndrome. Therefore, for patients suffering or suspected of suffering hypertriglyceridemia, blood triglyceride is desirably lowered to an appropriate level by use of a drug or through other methods.
Hyperinsulinemia is a disease caused by over-secretion of insulin from the islets of Langerhans of the pancreas, which over-secretion compensates hyperglycemia occurring in diabetes or a pre-diabetes stage. When insulin has been over-secreted, pancreatic hormone secretion ability and sugar-utilization in the peripheral tissue are impaired, and blood insulin is maintained at high level, thereby causing a variety of complications. For example, retinopathy, aggravation of nephropathy, and induction of differentiation of fat cells and other cells occur. Therefore, amelioration of hyperinsulinemia is effective for the prevention of such complications and obesity, particularly prevention of accumulation of visceral fat. Thus, there is the demand for a high-efficacy hyperinsulinemia-ameliorating agent.
The aforementioned pathological conditions and diseases are closely related to metabolic syndrome, whose diagnosis standards have recently been published, and are classified as life-style-related diseases including hyperlipidemia. According to the diagnosis standard, metabolic syndrome is defined as a condition in which visceral-fat-increased obesity is complicated with two or more of hyperglycemia, hypertension, and hyperlipidemia.
Statins (HMG-CoA reductase inhibitors) are administered to hyperlipidemia patients, since intense cholesterol-lowering action thereof is expected.
Statins are known to have an action on neutral lipid; specifically, a slight triglyceride-lowering action concomitant with a cholesterol-lowering action (see, for example, Non-Patent Document 1). However, when statin is used singly, triglyceride-lowering action thereof is insufficient. Thus, there has been proposed use of statin in combination with a triglyceride-lowering agent; for example, a fibrate-type drug. However, rhabdomyolysis has been reported to occur as an adverse side effect mainly in kidney disorder patients, when such a fibrate-type drug having strong triglyceride-lowering action and statin are used in combination. Thus, this combined administration must be carried out very carefully.
Statins are also known to have an action on insulin; specifically, a slight insulin-resistance-ameliorating action concomitant with a cholesterol-lowering action (see, for example, Non-Patent Document 2). However, no effect of statins has been known to ameliorate hyperinsulinemia. When statin is used singly, the insulin-resistance ameliorating action thereof is insufficient. Thus, there have been proposed the use of statin in combination with other insulin-resistance-ameliorating agents such as metformin or glitazones and use thereof in combination with a hypoglycemic agent such as a sulfonylurea agent. However, when statin is used with another agent such as an insulin-resistance-ameliorating agent or a hypoglycemic agent, control of blood sugar level is difficult, possibly causing a fatal hypoglycemia condition. Thus, this combined administration must also be carried out very carefully.
Generally, in many patients suffering hyperlipidemia, diabetes, metabolic syndrome, etc., hypertriglyceridemia occurs due to obesity or impairment in a metabolic function. Also, hyperinsulinemia occurs in many cases due to insulin secretion hyperfunction of the pancreas, which hyperfunction compensates for hyperglycemia. Therefore, there has been the demand for a drug which reduces adverse side effects and which promotes effective triglyceride-lowering action, as well as the demand for a drug which promotes hyperinsulinemia-ameliorating action, which drugs are used in combination with stain serving as a hyperlipidemia-treating agent.
Meanwhile, calcium antagonist is employed as a therapeutic agent for hypertension and angina pectoris, but neither triglyceride-lowering action nor hyperinsulinemia-ameliorating action is envisaged in use thereof, in view of the action mechanism of the antagonist. Furthermore, amlodipine besylate—a type of calcium antagonist—has been reported to increase the triglyceride level of hypertension patients (see Non-Patent Document 3). Also, amlodipine has been reported to give no significant effect on the plasma triglyceride level of hypertension patients (see Non-Patent Document 4). In animal models, when administered to fructose-loaded hypertriglyceridemia rats, amlodipine besylate has no significant triglyceride-lowering action or hyperinsulinemia-ameliorating action (see Non-Patent Document 5).
Notably, the main action of calcium antagonist is a hypotensive activity on the basis of selectively binding to cell membrane potential-dependent calcium channel, reducing flow of calcium ions into cells, and relaxing smooth muscle of coronary and peripheral vessels. Hitherto, direct lipid-decomposing action has not been reported, nor has insulin biosynthesis, secretion, and decomposing action.
Statin has a cholesterol-lowering action, whereas a calcium antagonist has a hypotensive action. Therefore, in the clinical field, the two agents are administered in combination to patients suffering from both hyperlipidemia and hypertension. Some scientific documents report administration of atorvastatin and amlodipine in combination to patients suffering from a coronary arterial disease. In the studies, there has been found no difference between a plasma triglyceride level of the combined administration group and that of an atorvastatin single administration group (see Non-Patent Documents 6 and 7). In addition, these documents do not disclose plasma insulin level. Similarly, in animal models (genetically modified mice), no difference has been found between the plasma triglyceride level of an atorvastatin single administration group and that of an atorvastatin-amlodipine combined administration group (see Non-Patent Document 8). The document does not describe that the combined administration gives an effect on the plasma insulin level. Some patent publications (Laid-Open) disclose combined administration of statin and amlodipine (see Patent Documents 1 to 3). However, these patent documents are silent regarding the effects of combined administration of statin and a calcium antagonist on the triglyceride-lowering action and on hyperinsulinemia.    Patent Document 1:    International Publication WO99/11259, pamphlet    Patent Document 2:    International Publication WO99/11260, pamphlet    Patent Document 3:    International Publication WO99/11263, pamphlet    Non-Patent Document 1:    Clin. Cardiol., 19(9): 683-9, 1996    Non-Patent Document 2:    Therapeutic Research, 24: 1383-1389, 2003    Non-Patent Document 3:    Curr. Med. Res. Opin., 21(6): 951-8, 2005    Non-Patent Document 4:    Br. J. Clin. Pharmacol., 39(5): 471-6, 1995    Non-Patent Document 5:    Hypertension, 45: 1012-18, 2005    Non-Patent Document 6:    Am. J. Hypertension, 17: 823-827, 2004    Non-Patent Document 7:    Am. J. Cardiol., 95: 249-253, 2005    Non-Patent Document 8:    J. Mol. Cell. Cardiol., 35: 109-118, 2003